Polymorphic mixture of rifaximin and its use for the preparation of solid formulations

ABSTRACT

A Rifaximin polymorphic mixture of α/β form in a relative ratio of 85/15±3 and a process for its preparation. The polymorphic mixture of Rifaximin is for use as a medicament, in particular in the treatment of traveler&#39;s diarrhea and hepatic encephalopathy. A pharmaceutical composition comprises the polymorphic mixture of Rifaximin as active ingredient, in particular, a solid formulation, more in particular, a film coated tablet. A polymorphic form of crude wet rifaximin and of purified wet rifaximin their use are used as intermediates in a process for the preparation of Rifaximin polymorphic mixture of α/β form in a relative ratio of 85/15±3.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/300,879, filed Sep. 30, 2016, which is now U.S. Pat. No. 10,556,915,which is the U.S. National Phase of International Application No.PCT/EP15/056304, filed on Mar. 24, 2015, and claims priority to EuropeanApplication No. 14162587.1, filed on Mar. 31, 2014, the contents of eachare incorporated by reference herein, in their entirety and for allpurposes.

FIELD OF THE INVENTION

The present invention relates to the field of organic chemistry, inparticular of medicinal chemistry, more in particular to the field ofthe manufacture of Active Pharmaceutical Ingredients (APIs).

BACKGROUND OF THE INVENTION

Rifaximin (compound identified by CAS registry number 80621-81-4) is anon-absorbable semisynthetic rifamycin antibiotic disclosed for thefirst time by Alfa Wasserman on 1981 (BE888895); this compound iscurrently utilized in therapy for the treatment of traveler's diarrheaand hepatic encephalopathy. Pharmacokinetics studies carried out onRifaximin confirmed that this compound is not absorbed from theintestine to any significant amount (Cellai, L.; Cerrini, S.; Brufani,M.; Marchi, E.; Mascellani, G.; Montecchi, L. Structure-activityrelationships in 4-deoxypyrido(1′,2′-1.2)imidazo(5.4-c) rifamycin SVderivatives. Chemioterapia (1983), 2(5. Suppl.: Mediterr. Congr.Chemother., Proc., 3rd, 1982), 53-4).

The structural formula of Rifaximin is the following

Due to this lack of systemic absorption Rifaximin has no applicationoutside the gastrointestinal tract and has an excellent safety profile.

Literature data confirm that this substance may be isolated in differentcrystalline forms identified with the letters of the Greek alphabet: theα, β, and γ forms were disclosed on 2004 (EP1557421 by Alfa Wasserman),the ε and δ forms on 2006 (EP1698630 by Alfa Wasserman), the ζ, η, αdry, ι forms on 2009 (W02009108730 by Salix Pharmaceuticals, Ltd.), Kand

forms on 2011 (WO2011153444 by Salix Pharmaceuticals, Ltd.). Moreover itis known that Rifaximin may exist in an amorphous form (W02008035109 byCipla Limited) and in an amorphous halo form (W02011080691).

Rifaximin in the polymorphic form α (the crystalline form present on themarket with the trade name of Xifaxan®) is considered a non-absorbabledrug, however the results of more recent pharmacological studies (seefor example G. C. Viscomi et al. Crystal forms of Rifaximin and theireffect on pharmaceutical properties Cryst Eng Comm, 2008. 10. 1074-1081)suggest that some of the above listed crystalline forms, for example theγ and the δ forms could be significantly absorbed.

Moreover, the above cited literature data indicate that the knownpolymorphic forms of Rifaximin may easily change their polymorphic formif exposed to different values of relative humidity: for example theanhydrous α- and δ-forms can be obtained by drying the monohydrateβ-form at different temperatures (30-65° C.) under vacuum and theanhydrous α form can be transformed into the corresponding monohydrate βform at a relative humidity of 56% after 40 hours (EP 1557421).

The present inventors found that in particular the crystallization anddrying conditions (using traditional static or dynamic drier, like abiconical drier) described in EP 1557421 showed to be critical sincethey did not consistently afford the desired α or α/β mixtures but theundesired γ polymorphic form or other polymorphic mixtures.

The control of the obtained solid state of Rifaximin polymorphic formsis usually performed by DRX spectroscopy, since the traditionaldifferential calorimetry analysis (DSC) and infrared spectroscopy (IR)are not able to discriminate and to quantify these polymorphs; also thewater content, as determined by Karl-Fisher, can give only indirectinformation on the solid state since cannot discriminate betweenadsorbed water and water in the lattice. Moreover, more than one hydrateand anhydrous forms for Rifaximin have been described.

The conversion of these polymorphic forms is therefore critical and needto be taken into account in order to guarantee the “consistency” of thecrystalline form in the Active Pharmaceutical Ingredient (API) and inthe drug product (Guidance for Industry ANDAs: Pharmaceutical SolidPolymorphism Chemistry, Manufacturing, and Controls Information. U.S.Department of Health and Human Services Food and Drug AdministrationCenter for Drug Evaluation and Research (CDER) July 2007).

It should be pointed out that the “consistency”, namely thereproducibility of the polymorphic form, is very important, especiallyin view of the regulatory requirements.

Finally, also for the preparation of the drug product the stability ofthe polymorphic forms of Rifaximin (for example film coated tablets) iscritical. The present inventors have experimental evidence that the wetgranulation procedures and tableting might modify the initial solidstate of this API: for example the wet granulation procedure ofRifaximin α form, a procedure that provides the use of purified water asbinding agent, afforded a sensible amount of Rifaximin β form (<50%) asresult of a change in the solid state of this API from anhydrous (αform) to hydrate (β form).

These findings indicate the need of putting appropriate manufacturingprocedures in place to consistently yield Rifaximin of the appropriatesolid state suitable to minimize changes of the solid state during thepreparation of the drug product.

SUMMARY OF THE INVENTION

It has now surprisingly been found that a new Rifaximin form, consistingof α/β mixture in a relative ratio of 85/15±3 can be preparedconsistently solving the problems of the prior art as discussed above.

It has also been found a process for the preparation of a consistentRifaximin α/β mixture in a relative ratio of 85/15±3 by crystallizationand drying of a new polymorphic form of Rifaximin (hereinafter alsonamed purified wet Rifaximin). Unexpectedly, this Rifaximin 85/15±3 α/βmixture is stable towards the influence of physical treatments employedfor the dry granulation and tableting.

The preparation of this consistent mixture Rifaximin α/β is obtainedthrough a drying procedure performed at 40° C. under nitrogen and understirring at atmospheric pressure of a new mixture of polymorphic forms.Rifaximin α/β mixture in a relative ratio of 85/15±3 obtained throughthe above described process can be utilized to prepare film coatedtablets using a dry granulation and tableting procedure without sensiblemodification of the relative ratio between the α and β polymorphic form.

Therefore, it is an object of the present invention a Rifaximinpolymorphic mixture of α/β form in a relative ratio of 85/15±3.

Another object of the present invention is a process for the preparationof said Rifaximin polymorphic mixture of α/β form in a relative ratio of85/15±3.

Another object of the present invention is a pharmaceutical composition,in particular a solid formulation, comprising the above polymorphicmixture of Rifaximin as active ingredient.

An object of the present invention is a film coated tablet comprisingthe above Rifaximin polymorphic together with a process for thepreparation of said film coated tablet.

Another object of the present invention is the above polymorphic mixtureof Rifaximin for use as a medicament, in particular in the treatment oftraveler's diarrhea and hepatic encephalopathy

Another object of the present invention is a polymorphic form of crudewet rifaximin obtained as intermediate in the process for thepreparation of the above Rifaximin polymorphic mixture of α/β form in arelative ratio of 85/15±3.

Another object of the present invention is a polymorphic form ofpurified wet rifaximin obtained as intermediate in the process for thepreparation of the above Rifaximin polymorphic mixture of α/β form in arelative ratio of 85/15±3.

Another object of the present invention is the use of the above crudewet rifaximin and/or of the above purified wet rifaximin as intermediatein a process for the preparation of Rifaximin polymorphic mixture of α/βform in a relative ratio of 85/15±3.

These and other objects of the present invention will be disclosed inthe detail in the following also by means of Figures and Examples.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Is a Calibration curve obtained using standard mixture of alphaand beta forms

FIG. 2. Is a DRX of wet Rifaximin before crystallization

FIG. 3. Is a DRX of wet Rifaximin: product recovered on the filter drierbefore drying

FIG. 4. Is a DRX of Rifaximin α/β polymorphic mixture in a relativeratio of 85/15±3

FIG. 5. Is a DRX of uncoated tablets of Rifaximin (dry granulation andcompaction)

FIG. 6. Is a DRX of Cellulose Microcrystalline

FIG. 7. Is a DRX of Polyvinyl Alcohol

FIG. 8. Is a DRX of FeO (red iron oxide)

FIG. 9. Is a DRX of Gliceryl palmitostearate

FIG. 10. Is a DRX of Sodium starch glycolate

FIG. 11. Is a DRX of Polyethylene glycol 6000

FIG. 12. Is a DRX of Hydrated Silicon Dioxide

FIG. 13. Is a DRX of Talc

FIG. 14. Is a DRX of Titanium dioxide

FIG. 15. Is a DRX of Rifaximin alpha form

FIG. 16. Is a DRX of Rifaximin beta form

FIG. 17. Is a monodimensional ¹H-NMR (500 MHz) spectrum of Rifaximinpolymorphic mixture in tetradeuterated methanol.

DETAILED DESCRIPTION OF THE INVENTION

Within the frame of the present invention we define “polymorphism” theability of a solid material to exist in multiple forms or crystalstructures known as polymorphs.

Within the frame of the present invention the terms “consistency” and“consistent” are used as synonyms of “reproducibility” and“reproducible”. These terms are well understood by the person ofordinary skill in the art, in particular of the manufacture of APIs,also in view of the requirements of Regulatory Authorities.

According to the present invention, the process for the preparation ofRifaximin α/β polymorphic mixture in a relative ratio of 85/15±3comprises the following steps:

a) reacting a molar equivalent of Rifamycin O with 2 or 3 equivalents of2-amino-4-methylpyridine in a solvent mixture of water and ethyl alcoholin a volumetric ratio between 1:2 and 1:3, at a temperature between 20°C. and 30° C., to give a reaction mass;b) treating said reaction mass at 20-30° C. with ascorbic acid, thenwith a mixture of water and ethyl alcohol and concentrated aqueoushydrochloric acid, adjusting pH of the reaction mass to a final value of6.0-6.5, to obtain a suspension;c) filtering the suspension, washing the resulting solid with awater/ethyl alcohol solvent mixture to obtain crude wet Rifaximin;d) purifying crude wet Rifaximin by dissolving it in ethyl alcohol at atemperature between 50° C. and 60° C. and precipitating wet purifiedRifaximin by adding water and by lowering the temperature of thesuspension to between 28-33° C. under stirring for a period of timebetween 1-3 hours, cooling down the crystallization mixture to 20-25° C.under stirring for a period of time comprised between 1 and 2 hours andfinally cooling down the crystallization mixture to 0-5° C. understirring for a period of time to obtain a precipitate;e) filtering the suspension on a filter drier, washing the resultingsolid with water, andf) drying under stirring, under a inert gas flow at normal pressure, ata temperature comprised between 38 and 42° C. for a period of time toreach a final water content of 6±2%.

It is understood that all the values and intervals disclosed in theprocess of the present invention must not be intended as absolute. Anyvalue or interval must be understood by the person of ordinary skill inthe art as “about”. The term “about”, as currently intended, means thatany value herein disclosed not necessarily must be exactly taken per se,but that a deviation from this value is within the scope of the presentinvention, provided that the technical effect herein disclosed isachieved.

In a preferred embodiment of the process according to the presentinvention, the concentration of rifamycin O in step a) is comprisedbetween 0.2 and 0.4 M, the relative ratio between water and ethylalcohol is 1:2.3 and the temperature of reaction is of 23° C.

Preferably, the molar equivalent of ascorbic acid with respect to theinitial amount of rifamycin O in step b) is comprised in a range of 1/8to 1/10. The relative ratio between water and ethyl alcohol is comprisedin a range of 65/35 to 60/40 and the final concentration of hydrochloricacid is comprised between 2.5M and 3.5M.

Preferably, the relative ratio between the initial amount of Rifamycin Oand the filter surface of the filter drier in the step e) is comprisedbetween 1 g/0.6 cm² and 1 g/1.57 cm²

Preferably, the stirring rate in step f) is of about 15 rpm/minute andthe preferred temperature is of 40° C. and the drying time can betypically maintained for a time interval ranging from 20 to 25 hours,more preferably from about 21 hours. Preferably the inert gas of step f)is nitrogen.

The step f) can be optionally performed in a discontinuous way withoutaffecting the relative ratio of the obtained polymorphic forms ofRifaximin.

The crude wet Rifaximin recovered from step c) according to the presentinvention is characterized by an X-Ray spectrum with characteristic2theta values at (relative intensity): 4.88 (87%), 7.78 (74%), 12.76(57%), 14.08 (59%), 14.66 (46%), 17.80 (50%), 18.34 (69%), 19.78 (80%),21.22 (70%), 21.92 (74%), 23.18 (80%), 25.30 (100%) (FIG. 2).

The purified wet Rifaximin recovered from step e) according to thepresent invention is characterized by an X-Ray spectrum withcharacteristic 2theta values at (relative intensity): 5.78 (15%), 7.32(27%), 8.16 (40%), 9.20 (44%), 10.74 (50%), 17.56 (42%), 18.04 (75%),18.70 (100%), 20.02 (54%), 21.24 (73%), 22.32 (54%), 23.62 (46%), 25.66(61%) (FIG. 3).

The Rifaximin α/β polymorphic mixture 85/15±3 recovered from step f)according to the present invention is characterized by an X-Ray spectrumwith characteristic 2theta values at (relative intensity): 5.32 (11%),5.78 (19%), 6.50 (27%), 7.24 (45%), 7.82 (61%), 8.80 (100%), 10.50(59%), 11.02 (35%), 11.58 (32%), 13.08 (20%), 14.42 (26%), 17.32 (48%),17.68 (93%), 18.58 (79%), 19.52 (61%), 21.04 (52%), 21.60 (30%), 21.92(46%) (FIG. 4).

Generally, in the process according to the present invention, RifamycinO is dispersed in a mixture of demineralized water and ethyl alcohol inthe proportions above disclosed under stirring at 20-30° C., then2-amino-4-methylpyridine was loaded. The reaction mixture is maintainedunder stirring for a sufficient time to let the reaction, preferably for20-25 hours at 20-25° C.

After this period, L-ascorbic acid is added to the reaction mixture andthe pH corrected under stirring at 20-30° C. to a final value of 6.0-6.5by addition of 3M HCI in a water/ethanol solution (for example 62/38v/v). The reaction mixture is then cooled down at 8-12° C. maintainedunder stirring for a time sufficient to obtain a massive precipitation,usually 2 hours, and filtered the suspension on a Büchner (or otherequivalent) filter. The solid recovered on the filter was washed with anethanol/water mixture, for example 1/1 v/v and utilized as such in thenext step of crystallization.

The wet product recovered in the previous step is then dispersed inethanol and heated under stirring until a solution is obtained.Conveniently, heating is around 50-60° C. Subsequently, water is addedmaintaining the heating temperature, conveniently around at 50-60° C.The reaction mixture is cooled down to 28-33° C. to afford aprecipitate. The obtained suspension is maintained at 28-33° C. understirring for 2 hours, then cooled down at 20-25° C. and stirred at thistemperature for 1 hour and finally to 0-5° C. and stirred at thistemperature for a time necessary to obtain a massive precipitate,usually 1 hour. The obtained suspension is filtered and the solid sorecovered washed with water.

The purified wet Rifaximin recovered on the filter (new polymorphic formdefined by characteristic DRX (powder) spectrum; FIG. 3) is dried understirring at the temperature of 40° C. and under an inert gas flow (forexample for 21 hours) to reach a water content of 6.0±2% (determined byKarl Fisher). Rifaximin as α/β polymorphic mixture with a relative ratioof 85/15±3 is so obtained.

The process according to the present invention shows advantageousconsistency, affording the same polymorphic mixture with a variabilityof ±3% (from 82/18 to 88/12 of α/β polymorphic mixture) after a numberof repetitions.

Advantageously, the α/β polymorphic mixture obtained by the process ofthe present invention is stable when stored at room temperature up to 6months.

The Rifaximin mixture disclosed in the present invention is very usefulin the preparation of pharmaceutical compositions containing it asactive ingredient.

Said compositions comprise any of conventional vehicles, excipients,formulative ingredients and can be prepared according to the generalknowledge in this art. A general reference can be found for example inRemington “The Science and Practice of Pharmacy, 21st editionPharmaceutical Press.

In a preferred embodiment of the present invention, the Rifaximinmixture above disclosed is useful for the preparation of a film coatedtablet.

Said compositions can be prepared according to the general knowledge inthis art. A general reference can be found for example in PharmaceuticalManufacturing Handbook: Production and Processes, Shayne Cox Gad, JohnWiley & Sons, 2008.

Said compositions comprise any of conventional vehicles, excipients,formulative ingredients used in the technology of coating of solidpharmaceutical compositions, for example talc, microcrystallinecellulose, glycerol palmitostearate, sodium starch glycolate, hydratesilicon dioxide.

Accordingly, it is another object of the present invention a process forthe preparation of a film coated tablet comprising the following steps:

a′) mixing Rifaximin α/β polymorphic mixture in a relative ratio of85/15±3 with suitable excipients at room temperature to give a anhomogeneous mixture;

b′) processing said mixture from step a′) with drygranulation/compaction and sieving it on a 20 mesh sieve to obtain ablend;

c′) compressing the blend obtained at step b′) to afford tablets with adisintegration time in purified water at 37° C. of 1′20″±15″;

d′) coating the tablets obtained in step c′) using suitable coatingagents, plasticizers and opacifiers.

The step a′) can be realized preferably utilizing excipients likemicrocrystalline cellulose, sodium starch glycolate, glycerolpalmitostearate, hydrated silicon dioxide and talc in a relative ratioranging from 33±3%, 4±0.4%, 4.9±0.5%, 0.5±0.05% and 3.0±0.3%

The step d′) can be realized preferably utilizing coating agents likepolyvinyl alcohol or hydroxypropyl methyl cellulose, plasticizers likepolyethylene glycol, dibutyl sebacate, citrate esters, triacetin andopacifiers like titanium dioxide and aluminum lacquers more preferablypolyvinyl alcohol, polyethylene glycol and titanium dioxide.

The uncoated tablets recovered from step c′) according to the presentinvention is characterized by an X-Ray spectrum with characteristic2theta values at (relative intensity): 5.28 (15%), 5.78 (23%), 6.52(46%), 7.26 (47%), 7.88 (75%), 8.82 (42%), 10.52 (46%), 11.02 (45%),11.58 (40%), 13.12 (37%), 14.48 (42%), 17.38 (56%), 17.72 (62%), 18.62(93%), 19.54 (72%), 21.10 (87%), 21.64 (82%), 22.00 (100%). Thefollowing diagnostic peaks of the employed excipients are alsodetectable on the DRX spectrum (2theta values, in brackets the relativeintensity of the diffraction peaks): 19.10 (50%) and 28.72 (40%) fortalc; 22.36 (99%) microcrystalline cellulose; 21.10 (87%) for glycerolpalmitostearate; 45.74 (36%) sodium starch glycolate; hydrate silicondioxide is amorphous and does not present diffraction peaks (FIG. 5).

In an exemplary embodiment of the present invention, a film coatedtablet comprising the above Rifaximin α/β polymorphic mixture, isprepared starting from a tableting mixture. The Rifaximin α/βpolymorphic mixture is mixed with conventional excipients known in theart of film coated tablets, for example cellulose microcrystalline,sodium starch glycolate, glyceryl palmitostearate and talc. Otherexcipients can be used according to the general knowledge in this art.The components are mixed for a time sufficient to obtain a homogeneousmixture in a suitable mixing device. Typically, few minutes aresufficient. The so obtained blend is then compacted/granulated by usinga conventional compactor (for example a WP50 N/75 compactor). Theobtained granules are finished with a sieve, with a suitable dimension,such as for example about 20 mesh. Lubricants are added, for example oneor more of glyceryl palmitostearate, talc, hydrated silicon dioxide.Conveniently also the excipients are previously sieved through a sieveof the same size of the granules. Mixing is carried out for a suitabletime, typically few minutes, in a suitable mixer. The blend iscompressed by means of a rotary tableting machine or any otherconventional equipment.

In a preferred embodiment, the tablets according to the presentinvention have the following technological characteristics:Hardness—18.49±1.30 Kp; Thickness—5.48±0.06 mm; Friability—0.058%;Disintegration in purified water at 37° C.—1′20″.

Film coating is carried out according to any suitable known technique,for example a coating pan by spraying a water suspension containing afilm coating agent (such as polyvinyl alcohol, or other equivalent) andplasticizers (such as polyethylene glycol or other equivalent), and ifdesired an opacifier (for example titanium dioxide) and/or a coloringagent (for example red iron oxide). Preferably, the coated tablets areprepared keeping the tablet bed at a temperature below 40° C. for theentire coating process.

Packaging is done according conventional manufacturing practice, forexample aluminum/plastic blister.

According to another object of the present invention, the polymorphicmixture of Rifaximin herein disclosed is for use as a medicament, inparticular for the treatment of traveler's diarrhea and hepaticencephalopathy.

The dosage, way of administration and clinical indication can be decidedby the expert of the art, based on the general knowledge, for example asshown in U.S. Pat. Nos. 7,902,206, 7,906,542, 8,158,644 and 7,928,115for coated and uncoated tablets, hard and soft gelatin capsules andpowders in sealed packets.

The following Examples further illustrate the invention.

Materials and Methods

X-Ray Diffraction spectra were registered by means of diffractometer(Rigaku-D-Max) from a start angle [½ 2-theta] of 5.000 to 60.000. Thediffraction diagrams were obtained employing a Cu anode (Kα=1.54060 Åand Kα=1.54439 Å). The relative ratio between alpha and beta polymorphicforms were determined by DRX (powder) using a calibration curve obtainedusing two samples of Rifaximin prepared by mixing pure alpha (DRX:Enclosure 15) and pure beta (DRX: Enclosure 16) forms in a relativeratio of 80/20 and 90/10 (these samples were prepared according toEP1557421). The diagnostic diffraction peaks considered in order toquantify the relative ratio between the alpha and the beta form are thefollowing:

-   -   Alpha form: diffraction peak at about 5.9 2theta    -   Beta form: diffraction peak at about 5.3 2theta

The calibration curve was prepared taking into consideration theintensity of the diffraction peak at 5.2 2theta (beta form) divided forthe intensity of the diffraction peak at 5.9 2theta (alpha form) (seeFIG. 1).

Example 1 Preparation of Crude Wet Rifaximin

Rifamycin O (50 g) was dispersed in a mixture of demineralized water (60ml) and ethyl alcohol (140 ml) under stirring at room temperature, then2-amino-4-methylpyridine (20.8 g) was loaded. The reaction mixture ismaintained under stirring at 20-30° C. for 20-23 hours.

After this period, L-ascorbic acid (1.4 g) was added to the reactionmixture and the pH corrected under stirring at room temperature to afinal value of 6.0-6.5 by addition of 3M HCI water/ethanol 62/38 v/vsolution. The reaction mixture was then cooled down at 8-12° C.maintained under stirring for 2 hours and filtered on a Büchner filter.The solid recovered on the filter (about 90.2 g of wet product with 54%of loss on drying; 30% of water content) was washed with a 1/1ethanol/water mixture (242 ml) and utilized as such in the next step ofcrystallization. This new polymorphic form is defined by the DRXreported in FIG. 2. The characteristic 2theta values for thispolymorphic form are (relative intensity): 4.88 (87%), 7.78 (74%), 12.76(57%), 14.08 (59%), 14.66 (46%), 17.80 (50%), 18.34 (69%), 19.78 (80%),21.22 (70%), 21.92 (74%), 23.18 (80%), 25.30 (100%).

Example 2

Preparation of Rifaximin α/β polymorphic mixture in a relative ratio of87/13 from crude wet Rifaximin

The wet crude Rifaximin recovered in the previous step was dispersed inethanol (80.5 ml) and heated under stirring at 50-60° C. (a solution wasobtained) then water was added (16.5 ml) maintaining the temperature at50-60° C. The reaction mixture was cooled down to 28-33° C. to afford aprecipitate. The obtained suspension was maintained at 28-33° C. understirring for 2 hours, then cooled down at 20-25° C. and stirred at thistemperature for 1 hour and finally to 0-5° C. and stirred at thistemperature for 1 hour. The obtained suspension was filtered on alaboratory filter drier (GFD® Mod. PF00002ATEX) and the solid sorecovered washed on the filter with water (62.2 ml).

The wet product recovered on the filter (defined by DRX powder andidentified by us as purified wet Rifaximin; FIG. 3) was dried understirring (15 rpm/m) at the temperature of 40° C. and under a nitrogenflow for 21 hours to reach a water content of 6.0% (determined by KarlFisher). 32 g of Rifaximin as α/β polymorphic mixture with a relativeratio of 87/13 was obtained (determined by DRX powder as reported in theFIG. 4). The physico-chemical data of the obtained sample are inagreement with the proposed structure and with published literature data(R. Stradi et al. Journal Pharmaceutical and Biomedical Analysis, 51(2010), 858-865); Enclosed the monodimensional ¹H-NMR (500 MHz) spectrumof the obtained sample in tetradeuterated methanol (FIG. 17).

The relevant peaks of the DRX spectrum of the purified wet Rifaximinrecovered on the filter are detectable at the following 2theta values(relative intensity): 5.78 (15%), 7.32 (27%), 8.16 (40%), 9.20 (44%),10.74 (50%), 17.56 (42%), 18.04 (75%), 18.70 (100%), 20.02 (54%), 21.24(73%), 22.32 (54%), 23.62 (46%), 25.66 (61%) (FIG. 3).

The relevant peaks of the DRX spectrum of Rifaximin α/β polymorphicmixture in a relative ratio of 87/13 are detectable at the following2theta values (relative intensity): 5.32 (11%), 5.78 (19%), 6.50 (27%),7.24 (45%), 7.82 (61%), 8.80 (100%), 10.50 (59%), 11.02 (35%), 11.58(32%), 13.08 (20%), 14.42 (26%), 17.32 (48%), 17.68 (93%), 18.58 (79%),19.52 (61%), 21.04 (52%), 21.60 (30%), 21.92 (46%) (FIG. 4).

Example 3 Consistency of the Polymorphic Mixture

The consistency of this procedure was checked repeating the processthree times affording the same polymorphic mixture with a variability of±3% (from 82/18 to 88/12 of α/β polymorphic mixture).

Example 4 Stability of the Polymorphic Mixture

The stability of a sample of Rifaximin α/β polymorphic mixture 88/12using as primary packaging double polyethylene bags at room temperaturewas confirmed by repeating the DRX (powder) analysis of the same batchat time=0 and after 3 and 6 months

Example 5 Dry Granulation and Tableting of Rifaximin α/β PolymorphicMixture in a Relative Ratio of 85/15±3

Tableting Mixture Production

Rifaximin α/β polymorphic mixture in a relative ratio of 85/15±3 (452.86g), Cellulose microcrystalline (259.90 g/Vivapur PH 102), Sodium starchglycolate (16.824 g), Glyceryl Palmitostearate (20.040 g/Precirol AT05)and Talc (1.203 g) are mixed for 5 minutes in a suitable mixing device.Blend is then compacted/granulated by using a compactor WP50 N/75.

Only a partial amount of these granules were utilized in the next step.The obtained granules (556.76 g) are finished with a 20 mesh sieve,added with Glyceryl Palmitostearate (14.87 g/Precirol AT05), Talc (4.68g), Hydrated Silicon Dioxide (2.97 g/Syloid 244), being all theexcipients previously sieved through a 20 mesh sieve, and mixed for 5minutes in a suitable mixer. The composition of the tableting mixture isas follows:

Rifaximin Tablet Composition Dry Granules

mg/tbs % w/w Rifaximin 550.0 54.1 Cellulose microcrystalline 340.0 33.4Vivapur PH 102 Sodium starch glycolate 42.0 4.1 Glyceryl Palmitostearate(Precirol 50.0 4.9 ATO 5) Hydrated Silicon Dioxide (Syloid 244) 5.0 0.5Talc 30 3 Total 1017 100Tableting Results

Blend is compressed by means of a rotary tablet machine Ronchi EA8equipped with 22×10 mm oval punches. Tablets with the followingtechnological characteristics were obtained: Hardness—18.49±1.30 Kp;Thickness—5.48±0.06 mm; Friability—0.058%; Disintegration in purifiedwater at 37° C.—1′20″.

The formulation for the coated tablets is reported below: the filmcoating was carried out in a suitable coating pan by spraying a watersuspension containing film coating agent (Polyvinyl alcohol) andplasticizers (Polyethylene Glycol) and opacifier (Titanium dioxide) andcoloring agent (Red iron oxide). The coated tablets were preparedkeeping the tablet bed at a temperature below 40° C. for the entirecoating process.

Rifaximin tablet composition after coating process is below reported.

mg/tbs % w/w Rifaximin 550.0 53.0 Cellulose microcrystalline (Vivapur PH102) 340.0 32.8 Sodium starch glycolate 42.0 4.0 GlycerylPalmitostearate (Precirol ATO 5) 50.0 4.82 Hydrated Silicon Dioxide(Syloid 244) 5.0 0.5 Talc 30 2.9 Polyethylene Glycol 6000 1.6 0.15Polyvinyl alcohol 15.0 1.4 Red iron oxide 0.4 0.04 Titanium dioxide 4.00.39 Total 1038 100

The obtained tablets before coating were mild grinded in a mortar andexamined by DRX (powder): these analyses confirm that Rifaximin presentsthe unchanged relative ratio between the α/β polymorphic form of 85/15±3(FIG. 5); on this DRX spectrum the following diagnostic peaks of theemployed excipients are detectable: 19.10 (50%) and 28.72 (40%) fortalc; 22.36 (99%) microcrystalline cellulose; 21.10 (87%) for glycerolpalmitostearate; 45.74 (36%) sodium starch glycolate; hydrate siliconDioxide is amorphous and does not present diffraction peaks.

In the enclosed FIGS. 6-14 are collected the DRX spectra of the employedexcipients; the diffraction peaks of the excipients do not interferewith the diagnostics peaks utilized for the relative quantitation ofRifaximin α and β forms (see materials and methods).

What is claimed:
 1. A Rifaximin polymorphic mixture of α/β form in arelative ratio of 85/15±3, characterized by an X-Ray spectrum withcharacteristic 2theta values at: 5.32, 5.78, 6.50, 7.24, 7.82, 8.80,10.50, 11.02, 11.58, 13.08, 14.42, 17.32, 17.68, 18.58, 19.52, 21.04,21.60, and 21.92.
 2. A pharmaceutical composition comprising thepolymorphic mixture of Rifaximin of claim 1, and a vehicle, excipient,or formulative ingredient.
 3. The pharmaceutical composition of claim 2,wherein the pharmaceutical composition is a solid pharmaceuticalcomposition.
 4. The pharmaceutical composition of claim 3, wherein thepharmaceutical composition is a film coated tablet.
 5. Thepharmaceutical composition of claim 2, wherein the pharmaceuticalcomposition comprises 550 mg of Rifaximin α/β polymorphic mixture of85/15±3.
 6. The pharmaceutical composition of claim 2, wherein thepharmaceutical composition further comprises excipients.
 7. Thepharmaceutical composition of claim 6, wherein the excipients comprisecellulose microcrystalline, sodium starch glycolate, glycerylpalmitostearate, hydrated silicon dioxide, and talc.
 8. Thepharmaceutical composition of claim 7, wherein the pharmaceuticalcomposition further comprises polyvinyl alcohol, polyethylene glycol,titanium dioxide, and red iron oxide.
 9. The pharmaceutical compositionof claim 8, wherein the pharmaceutical composition has a hardness of18.49±1.30 Kp, a thickness of about 5.48±0.06 mm, a friability of about0.058%, and a disintegration in purified water at 37° C. of about 1′20″.10. A tablet, comprising the Rifaximin polymorphic mixture of claim 1and a film coating.
 11. A Rifaximin polymorphic mixture of α/β form in arelative ratio of 85/15±3, characterized by an X-Ray spectrum withcharacteristic 2θ values at 5.32, 5.78, 6.50, 7.24, 7.82, 8.80, 10.50,11.02, 11.58, 13.08, 14.42, 17.32, 17.68, 18.58, 19.52, 21.04, 21.60,and 21.92, wherein said rifaximin polymorphic mixture is produced bydrying wet Rifaximin at atmospheric pressure, at a temperature between38 and 42° C. to reach a final water content of 6±2%.